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The Journal of Neuroscience, March 2, 2005, 25(9):2255-2266; doi:10.1523/JNEUROSCI.4372-04.2005

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Neurobiology of Disease
Ethanol-Responsive Brain Region Expression Networks: Implications for Behavioral Responses to Acute Ethanol in DBA/2J versus C57BL/6J Mice

Robnet T. Kerns,¹ Ajay Ravindranathan,³ Sajida Hassan,¹ Mary P. Cage,¹ Tim York,² James M. Sikela,⁴ Robert W. Williams,⁵ and Michael F. Miles¹

¹Departments of Pharmacology/Toxicology and Neurology and the Center for Study of Biological Complexity and²Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, ³The Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, California 94608, ⁴Department of Pharmacology and Human Medical Genetics, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado 80045, and ⁵Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.

Key words: ethanol; neurobiology; microarray; behavior; bioinformatics; mouse genetics

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Received Oct 21, 2004; revised January 11, 2005; accepted January 11, 2005.

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